Topical immunotherapy and compositions for use therein

ABSTRACT

The present invention is concerned with the use of at least one immunosuppressant, or a pharmaceutically acceptable salt, solvate of physiologically functional derivative thereof, in the treatment of topical immune disorders of the scalp, and scalp conditions, and compositions suitable for such use.

This application is a §371 National Stage Application of InternationalApplication No. PCT/GB2004/000474, filed on 6 Feb. 2004, claiming thepriority of Indian Patent Application No. 170/MUM/2003 filed on 6 Feb.2003.

The present invention is concerned with topical immunotherapy andcompositions suitable for use therein.

Topical immunotherapy can be used to describe topical treatment with anagent having immunomodulatory properties. Recently, topical formulationsincluding agents with direct immunosuppressive actions have been testedin diseases believed to have an immunological basis, especially atopicdermatitis and psoriasis. These topical immunosuppressive agents haveincluded tacrolimus and structurally related asomycin derivatives.

Tacrolimus is a hydrophobic macrolide immunosuppressant produced byStreptomyces tsukubaensis No. 9993. Tacrolimus,17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0^(4.9)]octacos-18-ene-2,3,10,16-tetraone,which is also known as FK-506 or FR-900506, has the following structuralformula:

Tacrolimus inhibits T-lymphocyte activation by first binding to anintracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12,calcium, cadmodulin and calcineurin is then formed and the phosphataseactivity of calcineurin is inhibited. The effect has been shown toprevent the dephosphorylation and translocation of nuclear factor ofactivated T-cells (NF-AT), a nuclear component thought to initiate genetranscription for the formation of lymphokines (such as interleukin-2,gamma interferon). Tacrolimus also inhibits the transcription for geneswhich encode IL-3, IL-4, IL-5, GM-CSF and TNF-alpha, all of which areinvolved in the early stages of T-cell activation. Tacrolimus inhibitsproliferation and selective cytokine expression in antigen stimulated Tcells in culture and also inhibits B cell proliferation at similarconcentrations. Immunosuppression with tacrolimus in humans preventsallograft rejection.

More particularly, tacrolimus inhibits T-lymphocyte activation, having adirect effect on T-lymphocytes so as to inhibit IL-2 transcription,which decreases responsiveness of T-lymphocytes to foreign antigens. Theaction of tacrolimus on atopic dermatitis may be related to alterationof antigen presenting cells, suppression of IL-2 and co-stimulatorymolecule expression, impairment of phenotypic and functionaldifferentiation of epidermal Langerhans' cells and suppression of Th1and Th2 cytokine induction in lymph node cells. The effect of tacrolimuson pruritis may be related to inhibition of histamine release from skinmast cells and impairment of de novo mast cell prostaglandin D2synthesis along with diminished release of histamine from basophiles.

Immunosuppression with tacrolimus in humans prevents allograftrejection. Tacrolimus is also reported as being used in the treatment ofrejection in transplantation and autoimmune diseases, and is routinelyused in transplantation of for example, the kidney, liver or heart.

Tacrolimus is available in both intravenous and oral formulation for theprevention of organ rejection after allogeneic liver or kidneytransplantation. Oral tacrolimus has been found to be useful in thetreatment of psoriasis, but potentially serious side effects, such asnephrotoxicity and hypertension, has limited its use for dermatologicindications by this route of administration. Topical formulations(ointments) have been extensively studied and reported to show positiveeffects in treatment of inflammatory skin diseases, such as atopicdermatitis and psoriasis. Tacrolimus administered topically (as anointment) has been reported to be safe and effective in the treatment ofskin diseases. It has been further reported that in patients with atopicdermatitis, tacrolimus does not alter collagen synthesis and is notatrophogenic.

U.S. Patent Application 2002052407, U.S. Pat. Nos. 6,187,756, 6,184,248and WO 98/09523 describe compositions of tacrolimus for use inneurological disorders and neurogenerative diseases.

EP 1092429 discusses pharmaceutical compositions and methods fortreating immune response associated disorders.

U.S. Patent Applications 2002173516 and 2002013340 describepharmaceutical compositions and methods for treating immune responseassociated diseases of the surface and anterior segment of the eye.

EP 1067926 and WO 99/51215 describe the use of tacrolimus as showinginhibitory activity on the production of nitric oxide.

Surprisingly, it has now been found that immunosuppressants as describedherein are particularly useful for treating topical immune disorders ofthe scalp, and scalp conditions. The present invention is, therefore,directed to such treatment and to compositions suitable for such use.

According to the present invention, therefore, there is provided atleast one immunosuppressant, or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof, for use in themanufacture of a medicament for the treatment of topical immunedisorders of the scalp, and scalp conditions.

An immunosuppressant suitable for use according to the present inventionis preferably selected from the group consisting of tacrolimus,cyclosporin, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof.

The present invention also provides a method for the treatment orprophylaxis of topical immune disorders of the scalp, and scalpconditions, which method comprises topically administering to the hairand scalp of a patient suffering from, or susceptible to, topical immunedisorders of the scalp, and scalp conditions, a therapeuticallyeffective amount of at least one immunosuppressant, or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

According to the above described method of the present invention, animmunosuppressant, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, can be topicallyadministered to the area of scalp affected by an immune disorder and assuch exert a therapeutic effect thereto. The treatment regime will bedependent on the patient, and severity of the scalp condition beingtreated, and will generally be at the discretion of an attendantphysician.

An immunosuppressant suitable for use in a method according to thepresent invention is preferably selected from the group consisting oftacrolimus, cyclosporin, or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof.

The term “physiologically functional derivative” as used herein denotesa chemical derivative of an immunosuppressant as described herein havingthe same or similar physiological function as the free baseimmunosuppressant and, for example, being convertible in the bodythereto.

Preferably, according to a use or method of the present invention, theimmunosuppressant is administered to a patient in the form of a haircare composition, such as a cream, spray, gel, shampoo or mousse, withthe use of a mousse composition generally being preferred.

Hair care preparations, and ingredients suitable for use therein, are ofcourse well known. Such preparations are generally aimed at providingcondition, shine, body and increased manageability to hair. There arerecognized categories of hair care compositions, including creams,sprays, gels, shampoos or mousses as referred to above. Hair sprays aregenerally composed of aerosolized copolymers, such aspolyvinylpyrrolidone, vinyl acetate and the like, and are generallyapplied following hair styling but may also function as a settinglotion. Hair gel preparations are similar to sprays in composition, butare in gel and alcohol free form, and can coat the hair shaft andrestore shine.

Hair mousse is foam released under pressure from an aerosolized can.Mousses can contain glossening and conditioning agents and can becolored to provide highlights. Hair mousses can also be employed toprovide fullness to hair, and achieve this more easily than hair gelsdue to their lower moisture content.

There is also provided by the present invention, therefore, apharmaceutical composition formulated for topical application to thehair and scalp of a patient, which composition comprises at least oneimmunosuppressant, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, together with at leastone carrier therefor, wherein said immunosuppressant is included in saidcomposition in a therapeutically effective amount so as to be capable ofexerting a therapeutic effect on topical immune disorders of the scalp,and scalp conditions, when administered to a patient sufferingtherefrom.

A composition according to the present invention can be provided as acream, spray, gel, shampoo or a mousse forming hair and scalp treatmentcomposition. Preferably, however, a composition according to the presentinvention is provided in the form of a mousse forming hair and scalptreatment composition for immune disorders of the scalp, and scalpconditions, wherein the composition comprises at least oneimmunosuppressant, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, together with at leastone carrier therefor, and which is formulated so as to be foamable ondispensing from a housing in which the composition can be packaged foradministration to a patient.

More particularly, there is provided by the present invention apharmaceutical composition formulated for topical application to thehair and scalp of a patient, which comprises at least oneimmunosuppressant, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, together with at leastone carrier therefor, wherein said immunosuppressant is included in saidcomposition in a therapeutically effective amount so as to be capable ofexerting a therapeutic effect on topical immune disorders of the scalp,and scalp conditions, when administered to a patient sufferingtherefrom, and further characterised in that the composition is providedas a mousse forming hair and scalp treatment composition formulated soas to be foamable on dispensing from a housing in which the compositionis packaged for administration to a patient.

Preferably, a mousse forming hair and scalp treatment compositionaccording to the present invention further comprises at least onepropellant. The propellant is the ingredient present in a mousse forminghair and scalp treatment composition according to the present inventionwhich is responsible for expelling, on administration to a patient, theother ingredients of the composition from a housing containing the same.Typically the propellant can be selected from the group consisting of1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoroethane(HFA 227), a combination of 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoroethane, monofluorotrichloromethane anddichlorodifluoromethane, and derivatives thereof, in particular1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoroethane(HFA 227). The use of 1,1,1,2-tetrafluoroethane (HFA 134a) is preferred.

Typically, a mousse forming hair and scalp treatment compositionaccording to the present invention can further comprise one or moreco-solvents. The composition may comprise both a propellant and aco-solvent, in which case it is desirable that the co-solvent has agreater polarity than the propellant. The co-solvent used may be anysuitable solvent, and typical co-solvents for use in the presentinvention include C₂₋₆ aliphatic alcohols and polyols, for exampleethanol, isopropanol and propylene glycol. Preferably the co-solvent isethanol. Generally the co-solvent is present in the range of 5 to 50% byweight of the total composition.

Suitably, a mousse forming hair and scalp treatment compositionaccording to the present invention may further comprise a surface-activeagent to stabilize the composition and for the lubrication of a valvesystem employed in a hair and scalp treatment product according to thepresent invention substantially as hereinafter described. Some of themost commonly used surface-active agents in mousse compositions are oilsderived from natural sources, such as corn oil, olive oil, cotton seedoil, sunflower seed oil, castor oil, cocoa butter, coconut oil, eveningprimrose oil, jojoba oil, linseed oil, palm oil, palm kernel oil, peanutoil and the like.

The immunosuppressant active ingredient in a mousse forming hair andscalp treatment composition according to the present invention ispreferably present at a concentration of 0.1 wt % to 5 wt % of the totalcomposition.

A mousse forming hair and scalp treatment composition according to thepresent invention may include further ingredients suitable for use in ahair care treatment composition of the type known in the art, and suchfurther ingredients can include petrolatum, waxes, lanolin, vegetableand mineral oils, plasticizers, preservatives, or other suitableingredient for a mousse composition. Such ingredients can add shine tohair and moisturize it, aid in straightening and decrease breakage, inaddition to the topical immunotherapy achieved further to the presenceof at least one immunosuppressant, or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof, in thecomposition substantially as hereinbefore described. The formulation mayfurther comprise colorants, fragrances and anti-oxidants, and siliconeand functional derivatives thereof to add lubricity, castor oil andderivatives thereof to aid in manageability and soluble glycoprotein tomaintain proper moisture balance and enhance shine.

A mousse forming hair and scalp treatment composition according to thepresent invention may be formulated as a hydrophobic or hydrophiliccream or gel, suitably with addition of a propellant known in the artand as described above.

The petrolatum and waxes are those commonly used by a person skilled inthe art in cream formulations and may include petroleum bases and waxesobtained from natural and synthetic origin, such as beeswax, carnaubawax, cetomacrogol waxes, paraffin waxes, lanolin, wool fat, ozoceriteand the like.

Mineral oils commonly used in mousse compositions include fatty acids,fatty alcohols, metallic stearates, monoalcohol esters, glycol esters,polyethylene glycol and its esters, sorbitan esters and the like.

Advantageously, a composition according to the present invention may beformulated substantially free of water, which can in certain embodimentsof the present invention be beneficial in terms of the stability of animmunosuppressant (especially tacrolimus), or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof, employed according to the present invention.

According to another aspect of the invention there is provided a hairand scalp treatment product, which comprises a composition substantiallyas hereinbefore described packaged in a housing (typically a can),provided with a dispensing mechanism for dispensing said composition tothe hair and scalp of a patient. Preferably the dispensing mechanism,and the ingredients of a composition according to the present invention,are such that a mousse can be generated on dispensing from the housing.

The present invention also provides a process of preparing a compositionas described herein, which process comprises providing at least oneimmunosuppressant, or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof, in the form of acomposition suitable for topical administration to the hair and scalp ofa patient substantially as hereinbefore described.

The present invention will now be further illustrated by the followingExamples, which do not limit the scope of the invention in any way.

EXAMPLES Example 1

Sr. No. Ingredients Quantity (% w/w) I CREAM  1. Tacrolimus 0.1-5%    2.Polyethylene glycol 4.00 400  3. Polysorbate 80 0.80  4. Methyl paraben0.20  5. Propyl paraben 0.02  6. Disodium edetate 0.10  7. Cetostearylalcohol 1.50  8. Cetomacrogol 1000 0.50  9. Light liquid paraffin 5.0010. Dimethicone 1.50 11. Propylene glycol 10.00 12. Triethanolamine q.s.to pH 6.0 13. Purified Water q.s. to 90.0 14. Ethanol 5-50% 15. Polyoxyl2-20% hydrogenated castor oil II PROPELLANT 16. Tetrafluoroethane 10.00(HFC-134a)

Example 2

Sr. No. Ingredients Quantity (% w/w) I CREAM  1. Cyclosporin 0.1-5%   2. Polyethylene glycol 4.00 400  3. Polysorbate 80 0.80  4. Methylparaben 0.20  5. Propyl paraben 0.02  6. Disodium edetate 0.10  7.Cetostearyl alcohol 1.50  8. Cetomacrogol 1000 0.50  9. Light liquidparaffin 5.00 10. Dimethicone 1.50 11. Propylene glycol 10.00 12.Triethanolamine q.s. to pH 6.0 13. Purified Water q.s. to 90.0 14.Ethanol 5-50% 15. Polyoxyl 2-20% hydrogenated castor oil II PROPELLANT16. Tetrafluoroethane 10.00 (HFC-134a)The ingredients as given above for Examples 1 and 2 were formulated soas to provide compositions according to the present invention, employingtechniques known in the art.

1. A pharmaceutical composition formulated for topical application tothe hair and scalp of a patient, which composition comprises atherapeutically effective amount of at least one immunosuppressantselected from the group consisting of tacrolimus, cyclosporin, or apharmaceutically acceptable salt thereof, together with at least onecarrier therefor,wherein the composition is provided as a mousse forminghair and scalp treatment composition formulated so as to be foamable ondispensing, from a housing in which the composition is packaged foradministration to a patient.
 2. A composition according to claim 1,which further comprises at least one propellant.
 3. A compositionaccording to claim 2, wherein said propellant is selected from the groupconsisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoroethane, a combination of1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoroethane,monofluorotrichloromethane and dichlorodifluoromethane, and derivativesthereof.
 4. A composition according to claim 3, wherein said propellantis 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoroethane.
 5. Acomposition according to claim 4, wherein said propellant is1,1,1,2-tetrafluoroethane.
 6. A composition according to claim 1, whichfurther comprises one or more co-solvents.
 7. A composition according toclaim 1, wherein said co-solvent is present in the range of 5 to 50% byweight of the total composition.
 8. A composition according to claim 1,which further comprises a surface-active agent.
 9. A compositionaccording to claim 8, wherein said surface-active agent is derived fromnatural sources including corn oil, olive oil, cotton seed oil,sunflower seed oil, castor oil, cocoa butter, coconut oil, eveningprimrose oil, jojoba oil, linseed oil, palm oil, palm kernel oil andpeanut oil.
 10. A composition according to claim 1, wherein saidimmunosuppressant is present at a concentration of 0.1 wt % to 5 wt % ofthe total composition.
 11. A composition according to claim 1, whichfurther comprises one or more of the following: petrolatum, waxes,lanolin, vegetable and mineral oils, plasticizers or preservatives. 12.A composition according to claim 11, wherein said petrolatum and waxesare selected from the group consisting of beeswax, carnauba wax,cetomacrogol waxes, paraffin waxes, lanolin, wool fat and ozocerite. 13.A composition according to claim 11, wherein said mineral oils areselected from the group consisting of fatty acids, fatty alcohols,metallic stearates, monoalcohol esters, glycol esters, polyethyleneglycol and its esters and sorbitan esters.
 14. A composition accordingto claim 1, which further comprises one or more colorants, fragrances,anti-oxidants, glossening and conditioning agents.
 15. A hair and scalptreatment product, which comprises a composition according to claim 1packaged in a housing provided with a dispensing mechanism fordispensing said composition to the hair and scalp of a patient.
 16. Aproduct according to claim 15, wherein said dispensing mechanism, andingredients of said composition, are such that a mousse is generated ondispensing from the housing.
 17. A process of preparing a compositionaccording to claim 1, which process comprises providing at least oneimmunosuppressant, selected from the group consisting of tacrolimus,cyclosporin, or a pharmaceutically acceptable salt thereof, in the formof a mousse suitable for topical administration to the hair and scalp ofa patient.
 18. A method for the treatment of topical immune disorders ofthe scalp, and scalp conditions, which method comprises topicallyadministering to the hair and scalp of a patient suffering from, topicalimmune disorders of the scalp, and scalp conditions, a compositionaccording to claim
 1. 19. A method according to claim 18, wherein saidcomposition is topically administered to an area of scalp affected bysaid topical immune disorder so as to exert a therapeutic effectthereto.
 20. A comoosition according to claim 1, wherein the compositionis substantially free from water.
 21. The hair and scalp treatmentproduct according to claim 15, wherein the composition free from water.